The present invention relates to compositions comprising xcex2-glucans and specific immunoglobulins, and to methods of therapy using the compositions.
xcex2-glucans are major structural components of yeast, fungi, and algae. Glucans are polymers of glucose that exist in both branched and unbranched forms. The polymers can exist as single strands with helical conformation, or as a complex of multiple strands that form a multi-stranded helix stabilized by hydrogen bonding.
xcex2-glucans have been shown to have an effect upon various aspects of the immune response, such as humoral and cell-mediated immunity. When xcex2-glucans are administered to experimental animals, the animals exhibit a wide range of immunomodulating and immunostimulating biological activities. These include nonspecific resistance against a variety of pathogenic challenges, promotion of wound healing, adjuvant effects when coadministered with any of bacterial, fungal, protozoal, or viral antigens, prolonged survival time in tumor-bearing animals, enhancement of bone marrow recovery and survival of lethally-irradiated mice, and reduction of serum cholesterol levels.
Administration of xcex2-glucans, particularly (1xe2x86x923)xcex2-D-glucans, enhances host resistance to a variety of experimentally-induced bacterial (S. aureus, E. coli, K. pneunomiae, S. pyogenes, M. tuberculosis, M. pyogenes), viral (Murin viral hepatitis, Venezuelan equine encephalomyelitis virus, HIV), fungal (C. albicans, C. neoformans) and parasitic infections. xcex2-glucans exert a significant beneficial effect on infectious episodes in animals with chemotherapy-induced immunosuppression.
All glucans, especially the soluble (1xe2x86x923)xcex2-glucans, and more particularly the branched (1xe2x86x923)xcex2-glucans, appear to be capable of inducing activation of macrophages and neutrophils, and are used as biological response mediators. Recent evidence suggests that the anti-infective efficacy of (1xe2x86x923)xcex2-glucans is attributable, at least in part, to macrophage activation induced by binding of the glucan to two specific receptors.
Studies of soluble xcex2-glucans in animals and humans have shown them to be non-antigenic and non-virulent. While xcex2-glucans induce toxicity, within certain ranges they can retain their activity in vivo without an unacceptable toxicity profile. xcex2-glucans which do not induce high levels of cytokines in vivo generally exhibit lower toxicity at higher amounts, but also generally exhibit lower potency. However, the potential for particulate glucans in immunotherapy is tempered by findings that their intravenous injection is associated with undesirable side effects, including hepatosplenomegaly, granuloma formation and microembolism.
Conventional treatment of bacterial infection entails the administration of antibiotics and/or standard IGIV. Standard IGIV is a composition comprising non-specific immunoglobulin. It contains antibodies typically found in a donor population which has not been stimulated by immunization with specific antigens. Combinations of xcex2-glucans with both antibiotics and standard IGIV have been reported. Reports of combinations of xcex2-glucans with standard IGIV and zinc describe improved response to xcex2-glucans as a result of a poorly-defined nonspecific stimulation of immune mechanisms by the standard IGIV and zinc, and combinations of the xcex2-1,3-linked triple-helical glucans extracted from S. cerevisiae with conventional antibiotic therapies have demonstrated increased efficacy as compared to the xcex2-glucan alone. No combination of xcex2-glucan with antibodies specific to a single species of pathogenic microorganisms has been described. Indeed, where standard immunoglobulins and glucans have been combined, non-specific stimulation of immune mechanisms by the standard immunoglobulin, rather than any specific effect, has been credited with any observed differences in overall effect vis-a-vis the use of glucan alone. Soltys et al., Veterinary Immunology and Immunopathology 42:379-388 (1994).
It is an object of the present invention to provide a composition, for use in a method of preventing or treating infection by a pathogenic microorganism, comprising a combination of xcex2-glucans and antibodies specific to a single species of pathogenic microorganism.
It is a further object of the present invention to provide a composition, for use in a method of preventing or treating infection by a pathogenic microorganism, comprising a combination of xcex2-glucans and antibodies specific to S. aureus. 
It is a particular object of the present invention to provide a composition, for use in a method of preventing or treating infection by a pathogenic microorganism, comprising a combination of xcex2-glucans and antibodies specific to S. aureus Type 5 and/or Type 8 antigens and/or antibodies specific to a S. aureus antigen that comprises xcex2-linked hexosamine, that contains no O-acetyl groups detectable by nuclear magnetic resonance spectroscopy and that reacts with antibodies to ATCC 55804. This latter antigen is denoted the 336 antigen and is disclosed in U.S. Pat. No. 5,770,208 issued Jun. 23, 1998.
It is yet another object of the present invention to provide a composition, for use in a method of preventing or treating infection by a pathogenic microorganism, comprising a combination of xcex2-glucans and antibodies specific to E. faecalis and/or E. faecium antigens, particularly those antigens disclosed in U.S. application Ser. No. 08/949,757 filed Oct. 14, 1997.
It is a further object of the present invention to provide a composition, for use in a method of preventing or treating infection by a pathogenic microorganism, comprising a combination of xcex2-glucans and antibodies specific to S. epidermidis antigens, particularly S. epidermidis antigens as disclosed in U.S. application Ser. No. 08/361,821.
These and other objects according to the invention are provided by a composition comprising a xcex2-glucan and specific antibodies. The specific antibodies preferably are specific to antigens from one or more of Staphylococcus and Enterococcus. When the specific antibodies are specific to Staphylococcus, they preferably are specific to one or more of Type 5 antigen or Type 8 antigen of S. aureus, a S. aureus antigen that comprises xcex2-linked hexosamine, that contains no O-acetyl groups detectable by nuclear magnetic resonance spectroscopy and that reacts with antibodies to ATCC 55804, and an antigen from S. epidermidis. When the specific antibodies are specific to Enterococcus, they preferably are specific to E. faecium or E. faecalis. Preferably, the xcex2-glucan is a soluble xcex2-glucan, and more preferably a chemically-derivatized xcex2-glucan, particularly one that is selected from the group consisting of carboxymethyl glucan, sulfoethyl glucan, glucuronoglucan, glucan sulfate, phosphorylated glucan, and glucan amine. Preferred xcex2-glucans are (1xe2x86x923)xcex2-glucans, particularly those that are branched.
The present invention also provides a kit that comprises a soluble xcex2-glucan, specific antibodies, and instructions for sequential administration of the xcex2-glucan and specific antibodies. The composition and kit are useful in a method of preventing or treating infection by a pathogenic microorganism, which comprises administering a soluble xcex2-glucan to a subject, and introducing specific antibodies to a pathogenic microorganism into said subject. The specific antibodies may be introduced in the subject by vaccinating the subject with a vaccine, or they may be introduced by administering specific antibodies to the subject. In the latter case, the specific antibodies preferably comprise hyperimmune immunoglobulin.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.